Chemical modifications of imidazole-containing alkoxyamines increase C-ON bond homolysis rate: Effects on their cytotoxic properties in glioblastoma cells - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Bioorganic and Medicinal Chemistry Année : 2019

Chemical modifications of imidazole-containing alkoxyamines increase C-ON bond homolysis rate: Effects on their cytotoxic properties in glioblastoma cells

Résumé

Previously, we described alkoxyamines bearing a pyridine ring as new pro-drugs with low molecular weights and theranostic activity. Upon chemical stimulus, alkoxyamines undergo homolysis and release free radicals, which can, reportedly, enhance magnetic resonance imaging and trigger cancer cell death. In the present study, we describe the synthesis and the anti-cancer activity of sixteen novel alkoxyamines that contain an imidazole ring. Activation of the homolysis was conducted by protonation and/or methylation. These new molecules displayed cytotoxic activities towards human glioblastoma cell lines, including the U251-MG cells that are highly resistant to the conventional chemotherapeutic agent Temozolomide. We further showed that the biological activities of the alkoxyamines were not only related to their half-life times of homolysis. We lastly identified the alkoxyamine ( RS/SR)-4a, with both a high antitumour activity and favourable logD(7.4) and pK(a) values, which make it a robust candidate for blood-brain barrier penetrating therapeutics against brain neoplasia.

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Chimie
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Dates et versions

hal-02491553 , version 1 (22-10-2021)

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Paternité - Pas d'utilisation commerciale

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Duje Buric, Christine Chacon, Gerard Audran, Diane Braguer, Sylvain R.A. Marque, et al.. Chemical modifications of imidazole-containing alkoxyamines increase C-ON bond homolysis rate: Effects on their cytotoxic properties in glioblastoma cells. Bioorganic and Medicinal Chemistry, 2019, 27 (10), pp.1942--1951. ⟨10.1016/j.bmc.2019.03.029⟩. ⟨hal-02491553⟩
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